Late relapses following reduced intensity allogeneic transplantation in patients with multiple myeloma: a long-term follow-up study.
Br J Haematol. 2013 Jan;160(2):199-206.
Sahebi F, Shen Y, Thomas SH, Rincon A, Murata-Collins J, Palmer J, Krishnan AY, Karanes C, Htut M, Somlo G, Forman SJ.
In this study, 60 patients with multiple myeloma received a RIC allogeneic SCT, either alone or after an autologous transplant. After a median follow-up of 9.8 years, OS at 7 years was 60%, and EFS 31%. Interestingly, the authors noted that 10% patients experienced very late relapses, between 6 and 12 years post-transplant. This observation argues against the achievement of definitive cure, even in patients who seem to be long-term survivors.

Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma.
Cancer. 2013 Jan 15;119(2):339-47.
White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE.
Patients with relapsed or refractory myeloma were randomized to receive bortezomib (53 patients) or bortezomib + bevacizumab (49 patients). The addition of bevacizumab did not improve clinical outcomes, because differences of response rate (51% in the bevacizumab-containing arm vs 43% in the bortezomib arm) and PFS (6.2 months in the bevacizumab-containing arm vs 5.1 months in the bortezomib only arm) were not statistically significant.

Randomized Phase II Study of Bortezomib, Thalidomide, and Dexamethasone With or Without Cyclophosphamide As Induction Therapy in Previously Untreated Multiple Myeloma.
J Clin Oncol. 2013 Jan 10;31(2):247-55.
Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL.
This study randomized patients with newly diagnosed myeloma to VTD (bortezomib, thalidomide, dexamethasone; 49 patients) or VTDC (VTD and cyclophosphamide 400 mg/m2) for four 21-day cycles before autologous stem cell transplant. VTDC increased toxicity without a significant improvement of clinical outcomes:
  - Rate of nCR/CR: 51% with VTD and 44% with VTDC
  - Response rate: 100% with VTD and 96% with VTDC
  - Overall survival at 3 years: 80% in both arms
  - Serious adverse events: 22% with VTD and 41% with VTDC

Targeted therapy of multiple myeloma.
Adv Exp Med Biol. 2013;779:197-221.
Dolloff NG, Talamo G.

Prognostic utility of intact immunoglobulin Ig'κ/Ig'λ ratios in multiple myeloma patients.
Leukemia. 2013 Jan;27(1):202-7.
Bradwell A, Harding S, Fourrier N, Mathiot C, Attal M, Moreau P, Harousseau JL, Avet-Loiseau H.

Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients.
Leukemia. 2013 Jan;27(1):213-9.
Ludwig H, Milosavljevic D, Zojer N, Faint JM, Bradwell AR, Hübl W, Harding SJ.

A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma.
Leukemia. 2013 Jan;27(1):220-5.
Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV.
In this randomized study of zoledronic acid (33 patients) vs zoledronic acid + thalidomide (35 patients) in smoldering myeloma, zoledronic acid alone did not produce anti-tumor responses.

Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach.
Biol Blood Marrow Transplant. 2013 Jan;19(1):69-74.
Blanes M, Lahuerta JJ, González JD, Ribas P, Solano C, Alegre A, Bladé J, San Miguel JF, Sanz MA, de la Rubia J.
The authors compared outcomes of a conditioning regimen with busulfan 9.6 mg/Kg + melphalan 140 mg/m2 (51 patients) vs the standard melphalan 200 mg/m2 (102 patients). No significant differences were found:
  - Response rates and CR rates were similar
  - Progression-free survival was similar (24 months with MEL vs 33 months with BU-MEL, p=0.1)
  - Transplant-related mortality: 2% with MEL and 4% with BU-MEL



Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen.
Eur J Haematol. 2013 Feb;90(2):157-61.
Kamimura T, Miyamoto T, Yokota N, Takashima S, Chong Y, Ito Y, Akashi K.
In a series of 15 patients, the authors demonstrated that injection site reaction were more frequent in the thigh compared with the abdomen (grade II: 9% vs 1%).
   Grade I =  tenderness with or without symptoms (pruritus, erythema, warmth)
   Grade II = pain, edema, phlebitis, lipodystrophy
It is possible that the more frequent occurrence in the thigh is due to the fact that the abdomen has more abundant adipose tissue, and therefore the local concentration of bortezomib in the subcutaneous tissues of the abdomen is more diluted.

A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial.
Blood. 2013 Feb 28;121(9):1517-23.
Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM.
In this study, 332 patients with newly diagnosed myeloma received an autologous stem cell transplant and they were randomized in two groups, one without maintenance therapy, and the other with maintenance, using thalidomide 200 mg daily and prednisone 50 mg every other day for 4 years or until disease progression.
Median follow-up was 4.1 years. Results:
  - Overall survival was similar (4-year OS was 68% with maintenance and 60% without maintenance, p=0.18)
  - Progression-free survival at 4 years was superior in the maintenance group (32% vs 14%, p<0.0001)
  - Median OS after relapse was 28 months with maintenance and 34 months with maintenance
  - Quality of life was worse in the maintenance group
The authors concluded that the benefit of post-transplant maintenance therapy with thalidomide and prednisone (= longer duration of disease control) was counterbalanced by negative aspects (= worse quality of life and no prolongation of life).


MARCH 2013

Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for heavily pretreated relapsed or refractory multiple myeloma.
Leuk Lymphoma. 2013 Mar;54(3):555-60.
Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Tiedemann R, Kukreti V.
In this retrospective study, VRD was administered in 30 patients with relapsed/refractory myeloma. Response rate was 47% (PR 37%, VGPR 10%). In 21 patients, disease progressed at a median of 3 months (range: 1.4-4.6 months).

Autologous stem cell transplantation: an effective salvage therapy in multiple myeloma.
Biol Blood Marrow Transplant. 2013 Mar;19(3):445-9.
Lemieux E, Hulin C, Caillot D, Tardy S, Dorvaux V, Michel J, Gastinne T, Rossi C, Legouge C, Touzeau C, Planche L, Loirat M, Lafon I, Moreau P.
In this retrospective study, 81 patients with myeloma relapsed after the first autologous transplant received a second autologous transplant as salvage therapy. The median progression-free survival after the first transplant was 40 months, and the median progression-free survival after the second transplant was 18 months. After multivariate analysis, the prognostic factors which predicted worse progression-free survival after the second transplant were:
  - Short duration of remission (less than 24 months) after first transplant
  - Suboptimal response (less than VGPR) after salvage therapy
  - No maintenance therapy after the second transplant
This study supports the view that duration of remission with a second autologous transplant done as salvage therapy is about half of that reached after the first transplant. From a practical point of view, these results seem to imply that a second autologous transplant should not be offered as salvage therapy to a relapsed patient unless the remission with the first transplant lasted more than 2 years.

A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma.
Br J Haematol. 2013 Mar;160(5):714-7.
Popat R, Plesner T, Davies F, Cook G, Cook M, Elliott P, Jacobson E, Gumbleton T, Oakervee H, Cavenagh J.
Resveratrol is a phytoalexin, naturally produced by several plants. Despite its demonstrated activity against myeloma cells in vitro, it lacked clinical efficacy (no response was observed) in this phase II trial of 24 patients with relapsed/refractory multiple myeloma.

Patterns of relapse and progression in multiple myeloma patients after auto-SCT: implications for patients' monitoring after transplantation.
Bone Marrow Transplant. 2013 Mar;48(3):419-24.
Zamarin D, Giralt S, Landau H, Lendvai N, Lesokhin A, Chung D, Koehne G, Chimento D, Devlin SM, Riedel E, Bhutani M, Babu D, Hassoun H.
After a retrospective study of 368 autologous stem cell transplant for myeloma done at MSKCC between 2001 and 2009, the authors found the first sign of relapse or progression after transplant is an increase of the myeloma markers in the serum in asymptomatic patients (85% of cases). Only 15% of patients had an aggressive disease that became clinically manifested by symptoms. Annual skeletal surveys were not useful in predicting disease relapse/progression.

Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02.
Blood. 2013 Mar 14;121(11):1968-75.
Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome.
Pomalidomide and weekly dexamethasone were given to 84 patients with myeloma refractory to both bortezomib and lenalidomide. Results:
  - Response rate: 35%
  - Median progression-free survival: 4.6 months
  - Median overall survival: 15 months



Giampaolo Talamo, MD